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How two U.S. patients changed the debate about using untested Ebola drugs

"Experts: Ebola Vaccine At Least 50 White People Away," The Onion reported on 30 July. As so often before, the satirical story turned out to be prophetic. Until last week, there appeared to be little hope that any experimental drugs or vaccines might be used in the worst Ebola outbreak ever, which according to the latest statistics from the World Health organization (WHO) has already sickened 1711 people and killed 932 in four West African countries. But the cases of two U.S. Ebola patients who were treated with an experimental antibody cocktail have suddenly upset that international consensus.

Just a few weeks ago, WHO said that using any of the experimental drugs or vaccines in the pipeline simply wasn't in the cards, because none of them have been through a phase I clinical study, the type of trial in which medical products are tested on healthy volunteers to study their toxicity. "Using an experimental vaccine on human beings in the middle of an outbreak in this case would not be ethical, feasible, or wise," a WHO representative e-mailed Science on 16 July.

But yesterday, the agency announced that it is convening a panel of medical ethicists to discuss whether experimental drugs or vaccines could be used after all. The announcement specifically mentioned the questions raised by the cases of Kent Brantly and Nancy Writebol, the U.S. health care workers who received a mix of monoclonal antibodies named ZMapp after they fell ill in Liberia. (Both were repatriated to the United States earlier this week, and both are recovering.) "We have a disease with a high fatality rate without any proven treatment or vaccine,” WHO assistant director-general Marie-Paule Kieny said. "We need to ask the medical ethicists to give us guidance on what the responsible thing to do is.”

At a hearing held today by the U.S. House of Representatives’ Subcommittee on Africa, Global health, Global Human Rights, and International Organizations, Tom Frieden, director of the U.S. Centers for Disease Control and Prevention, stressed that ZMapp represents more of a media phenomenon than a real scientific advance. “The plain fact is that we don’t know whether that treatment is helpful, harmful, or doesn’t have any impact,” Frieden says. “And we’re unlikely to know from two or a handful of patients whether it works.”

Armand Sprecher of Doctors Without Borders in Brussels says if Brantly had taken a turn for the worse and did rapidly improve after receiving the antibody cocktail, as some news reports have suggested, it would be very unusual in an Ebola case.

Sprecher concedes that the case—along with the loss of Sheik Umar Khan, Sierra Leone's chief Ebola fighter, who succumbed to the virus on 29 July—is "food for thought," and that he could see Zmapp or other products being used, for instance in an emergency clinical trial. Just a few weeks ago, Sprecher told Science that it might be counterproductive to bring experimental drugs or vaccines to the field; the affected population might see themselves as guinea pigs for Western companies, he said, which could increase hostility and complicate the fight against Ebola.

Although he still has those worries, a bigger concern now looming is that the treatment given to Brantly and Writebol apparently isn't being made available to Africans. This week, TheWall Street Journal reported that dying Liberian patients and their families are already asking for the therapy—and wondering why it appears to be for Americans only. "This is something that has made our job most difficult," the paper quoted Liberia's Assistant Health Minister Tolbert Nyenswah as saying.

"The shoe is on the other foot now," Sprecher says. "It's not that we would inflict horrible things on them, but that we failed to inflict good things on them."

"Things have clearly changed," adds virologist Robert Garry of Tulane University Health Sciences Center in New Orleans, Louisiana, who a few weeks ago had resigned himself—grudgingly, like many scientists—to the idea that no Ebola drugs or vaccines would be available during the current outbreak.

Still, the challenges are daunting. Several drugs and vaccines have shown promise in nonhuman primates, but none of them have successfully made it through phase I human trials. (A few vaccine candidates did go through phase I in the past—one of them among volunteers in Uganda—but all were later abandoned for scientific reasons.)

That didn't stop the two American patients from taking ZMapp. As health care workers, they understood the risk, Garry says. In 2009, a German researcher who accidentally pricked herself with a syringe holding Ebola took an experimental vaccine that hadn't been tested in humans either. (She didn't get sick, although scientists don't know whether the vaccine helped.) But whether products without any human safety data could also be used in Africa is a different question.

There's also the very practical problem of how much of any product is available. For instance, it's unclear how much Mapp Biopharmaceutical, the company developing ZMapp, has in store. At today's hearing, Frieden said did not know “definitively” how many courses were available. “I’ve heard that there are a handful,” he said, noting that he similarly did not know the quantity of other experimental Ebola treatments on hand. “This is rapidly changing information.” Frieden said the U.S. Food and Drug Administration (FDA) is “currently coordinating” with other agencies to see whether they can make new treatments available.

According to a scientist who knew the particulars of this use of ZMapp but asked not to be identified, the antibodies weren't produced under good manufacturing practices, a set of standards to guarantee quality and safety of medical products. But the source told ScienceInsider that FDA approved its use in the two patients after a request from a physician at Emory University in Atlanta who used the expanded access rules, which allow the emergency use of unapproved medicines on a "compassionate use" basis.

WHO hasn't announced who will be on its ad hoc ethics panel, which the agency says may meet as early as next week. One of the things the group may discuss is guidelines on just how to use any experimental product. Some experts say any treatments should not be given on a compassionate use basis, but should be part of a carefully conducted clinical trial, so as to learn as much about a compound’s efficacy as possible. "Otherwise the worry is that we will have tried these drugs, including putting people through the potential risk of experimental treatments, and still be none the wiser about which are effective," said Tom Solomon, director of the Institute of Infection and Global Health at the University of Liverpool in the United Kingdom, in a statement distributed today by the Science Media Centre.

But unlike most clinical trials for new drugs, the drug or vaccine wouldn't be compared with a placebo, Sprecher says. Given Ebola's horrendous fatality rate—well over 50% in the current outbreak—doctors would give the real treatment to anybody who meets certain eligibility criteria, he says, and see whether the case fatality rate drops.

Even the question of where to deploy a treatment raises difficult questions, Sprecher says. Normally, trials are set up in places where it's easy to recruit patients and where there are resources, staff, and expertise to monitor them. But using an Ebola treatment in one town and not in others would immediately trigger protests, he says. "You can't say: 'Let's try this at one site, and everyone else is the control group,' " Sprecher says. "You may have to do it at multiple sites."

WHO also has convened a committee to determine whether the Ebola outbreak constitutes a so-called Public Health Emergency of International Concern, a designation that, among other things, would allow WHO to issue travel recommendations to avoid spread of the disease. That panel, chaired by Sam Zaramba, a former official at the Ugandan Ministry of Health, will announce its decision at a press briefing on Friday.